The prognosis for patients with malignant brain tumors has improved minimally in the last two decades;median survival is less than one year for patients with malignant glioma, the most common primary brain tumor. These statistics provide a strong rationale for coordinated efforts to identify innovative approaches to treat these tumors. The unifying hypothesis of this program project is that novel therapeutic strategies that take into account the unique features of these tumors will induce tumor regression, and potentiate conventional therapies. Each project is translationally oriented, with a common goal of addressing fundamental biological issues relevant to tumor growth and evaluating innovative treatment approaches using a series of preclinical models, as a basis to identify promising strategies to advance into clinical therapies. Project 1 is based on the hypothesis that inhibition of aberrantly activated signal transduction pathways, or activation of apoptosis signaling, will induce glioma cell killing, potentially in a genotype-specific fashion, and that this approach will have independent activity in glioma models, and potentiate other approaches. Project 2 postulates that vaccination with glioma-associated antigen epitopes, in conjunction with systemic therapy designed to enhance immunoreactivity in the brain tumor microenvironment, will be an effective mechanism for antigen delivery to antigen-presenting cells, and that the conditions for immunization can be optimized using signaling or vector-mediated strategies that promote dendritic cell maturation and function, in collaboration with Projects 1 and 3. Project 3 postulates that gene delivery to the brain tumor microenvironment, using oncolytic Herpes virus vectors incorporating novel multigene constructs engineered to facilitate virus incorporation, spread, and transduction efficiency, can achieve tumor killing and enhance the effects of other treatment strategies. This project will also generate many of the vector constructs that will be used in Projects 1 and 2. The Administrative/Biostatistics/Clinical Support Core (A) provides essential infrastructure support for the activities of this program. The Cellular and Tissue Imaging Core (B) provides a panoply of advanced microscopic imaging capabilities used in each of the projects. The Immunological Monitoring and Cellular Products Laboratory Core (C) provides banking of tissue and serum samples, maintenance of cell lines, preparation of biological products, and therapeutic monitoring essential for the clinical protocols in this program. Relevance: Taken together, the multidisciplinary interactions that have evolved in this program optimize our chances to identify and refine promising approaches that can be applied clinically to improve the prognosis of patients with malignant gliomas.